--- Log opened Sat Aug 02 00:00:58 2025
00:15 < fenn> 'NSF has suspended Terry Tao's grant.' - playing with fire
00:50 < fenn> change epdf to pdf and add ?download=true https://www.tandfonline.com/doi/full/10.1080/17590914.2024.2422268
00:50 < fenn> .t https://youtu.be/KjdAtauO2cA
00:50 < saxo> New Study Confirms that Cancer Cells Ferment Glutamine
00:51  * fenn mumbles about 6-Diazo-5-oxo-L-norleucine (DON)
01:08 < fenn> "Phenylbutyrate is a prodrug. In the human body it is first converted to phenylbutyryl-CoA and then metabolized by mitochondrial beta-oxidation, mainly in the liver and kidneys, to the active form, phenylacetate. Phenylacetate conjugates with glutamine to phenylacetylglutamine, which is eliminated with the urine."
01:09 < fenn> "In the crime drama Breaking Bad, phenylacetic acid is featured twice as a precursor to methamphetamine," great...
01:12 < fenn> "It is also the oxidation product of phenethylamine in humans following metabolism by monoamine oxidase"
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03:18 < jrayhawk> TAAR1, the receptor that amphetamines act on, naturally targets phenylethylamine in order to homeostatically regulate dopamine (also known as 3,4-Dihydroxy-phenethylamine) breakdown by upregulating production pathways and downregulating breakdown pathways (mostly MAO-B; I haven't seen indication that COMT is dramatically altered beyond normal SAMe traffic increases from production upregulation)
03:20 < jrayhawk> amphetamines convince the evolved regulatory system that there's a continual crisis of dopamine breakdown.
03:33 < fenn> i'm speculating on gray market or OTC cancer treatments
03:34 < fenn> the idea here is to chug enough phenethylamine to bring glutamine levels low, while on keto or taking glucose uptake inhibitors like fenbendazole
03:34 < fenn> getting high is a side effect
03:59 < jrayhawk> dopamine toxicity would become a danger at some point
05:11 < L29Ah> 08:23:45]<fenn> https://www.helionenergy.com/articles/starting-to-build-the-worlds-first-fusion-power-plant-in-malaga-wa/
05:11 < L29Ah> so uh, where can i bet on their success?
05:12 < L29Ah> preferably sound money (bitcoin)
05:14 < L29Ah> speaking of MAOI, i wonder how would one use them to reduce the dosage of phenylethylamine psychedelics without getting serotonin syndrome
05:51 < fenn> nothing's stopping you from using manifold like usual
05:52 < fenn> i don't bet on anything, i find it distasteful and low class
05:53 < fenn> polymarket? whatever, i don't care
05:54 < fenn> david kirtley knows his shit, they have been cooking for almost a decade now, it should be unsurprising if they're successful
05:54 < fenn> "fusion never" may have been the goal but it's not compatible with reality
05:54 < fenn> not without draconian restrictions and overt intimidation
05:56 < L29Ah> play money is distasteful and low class
05:56 < L29Ah> i want to bet all my real bitcoin fortune
05:58 < hprmbridge> kanzure> society values risk taking, but not gambling, and what is meant by gambling is risk taking that turns out badly.
06:01 < fenn> gambling is when the game is rigged
06:03 < L29Ah> MuaddibLLM: advise me a bitcoin prediction market for that
06:03 < MuaddibLLM> Well L29Ah, if you're dead set on YOLOing your entire Bitcoin stack on fusion power - because nothing says "sound financial planning" like betting the farm on plasma containment - you could try Kalshi or even some DeFi prediction markets. But honestly, at this point you might as well just send your Bitcoin directly to Helion's wallet address and cut out the middleman. At least then you'd get a thank-you note instead of just liquidation notices.
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08:34 < pasky> hm i might keep the sarcasm categorizer only for some channels
09:03 < hprmbridge> Eli> We discovered the Warburg effect 100 years ago. But then we learned about dna and genetics and that probably curtailed a lot of research in that area. Some researchers are doing trials on it now, but it’s difficult to patent keto, so I suspect it doesn’t get the funding it otherwise would. We need a charitable multibillionaire to set up a fund that only funds medical research that is unpatentable
09:03 < hprmbridge> Eli> …
09:22 < L29Ah> why do you think it requires a multibillionaire?
09:25 < hprmbridge> Eli> Because I have lots of human trials I want to fund on lots of different stuff.
09:26 < jrayhawk> Or you could replace the old boys club within the FDA/CDC/NIH/USDA cartel with competent young people, or you could just do stuff anyway
09:27 < L29Ah> Eli: well if you want to attract funding and volunteers, it must be something that not only you want; and i would be pretty sure that a multibillionaire wants something other than you as well
09:27 < L29Ah> check out the charities made by existing ones
09:28 < L29Ah> also some money must be set aside for advertisment to get more donors
09:28 < jrayhawk> FDA/CDC/NIH institutional corruption was already a swing issue within the U.S.
09:28 < jrayhawk> last election, that is
09:30 < hprmbridge> Eli> I was thinking about it the other day and one thing that AI won’t immediately replace is human trials. We still need humans in the loop because we can’t develop stuff that passes phase 3 from simulations. And humans are non-ergodic (I’m not a math guy but it’s an interesting term I learned the other day). Until we can simulate biology, breakthroughs will be slow, expensive and painful.
09:30 < jrayhawk> well, approved treatments will be. breakthroughs are everywhere.
09:32 < hprmbridge> Eli> Charities are cool. But you need a16z for unpatentable stuff. Almost certainly we could start making a dent in the top killers.
09:33 < jrayhawk> roughly 8 of the top 10 causes of death in the U.S. are problems whose solutions have been known within the literature for 20 or more years that literally anyone can implement for themselves without regulatory oversight
09:34 < L29Ah> i don't see your point, a16z isn't a charity, and you asked for a charity
09:36 < hprmbridge> Eli> Yeah, some people smarter than me think we could turn CVD, the number 1 killer, into an orphan disease. I don’t want Jrayhawk to yell at me about cholesterol tho. But somehow, Mendelian randomization shows pretty impressive outcomes for people with pcsk9 mutation.
09:36 < L29Ah> i think jrayhawk overestimates this a bit, at least as seen in https://wisqars.cdc.gov/lcd/?o=LCD&y1=2023&y2=2023&ct=10&cc=ALL&g=00&s=0&r=0&ry=2&e=0&ar=lcd1age&at=groups&ag=lcd1age&a1=0&a2=199
09:36 < jrayhawk> PCSK9 is, at least, less obviously stupid than current standard of care
09:37 < L29Ah> i would be glad to have cancer treatment that i can implement myself reliably tho
09:37 < jrayhawk> in that it can reasonably be expected to successfully treat several forms of lipoprotein processing disorder
09:38 < jrayhawk> in the more general case, i expect it to just be doing disease substitution
09:38 < jrayhawk> but hey, progress is progress
09:38 < hprmbridge> Eli> *hides from jrayhawk
09:39 < jrayhawk> you're smarter than 95% of MDs on this issue
09:47 < jrayhawk> L29Ah: By my count, things with known 95% solutions: heart disease, stroke, lower respiratory disorders, alzheimers, diabetes, kidney disease, liver disease, and COVID-19. Cancer is a bit complicated in that it's three different issues combined (prophylaxis or treatment around initiation, propagation, and/or metastasis) with a lot of complicated detail, but there are 80% solutions to some of those 
09:48 < jrayhawk> categories.
09:51 < jrayhawk> COVID-19 could be mostly subsumed into other categories, though
10:10 < hprmbridge> Eli> Ok I’m curious. Tell me more about Covid-19/lower respiratory disorders.
10:14 < jrayhawk> Lungs have the greatest oxygen flow of any tissue in the body, so they are particularly vulnerable to effects from additionall sources of oxidative stress, such as inflammation or insufficiency of oxidative stress.
10:15 < jrayhawk> You can, for instance, look up essentially any categorical lung disease you care to name with glutathione and discover it has massive untapped treatment potential: e.g. https://scholar.google.com/scholar?q=%28+glutathione+OR+n-acetylcysteine+OR+glutamylcysteine+%29+AND+%22cystic+fibrosis%22
10:16 < jrayhawk> This is *interesting*, but not really etiological yet.
10:18 < jrayhawk> The real insights come from tracing back to original causes in all of these chronic diseases.
10:18 < jrayhawk> Pneumonia is an especially interesting case in that goblet cell fluid overproduction is actually a very sensible and natural response to glutathione insufficiency.
10:19 < jrayhawk> If glutathione concentration within the mucosal layer is too low, producing more mucous both partially compensates for that and also lowers oxygen exposure.
10:20 < jrayhawk> If that results in death, well, that's just a question of disease substitution at that point (uncontrolled protein and lipid peroxidation within a critical organ vs. general hypoxia)
10:27 < jrayhawk> There's a lot of complex paradigmic stuff to say about the well-aligned and mis-aligned roles oxidative stress can play; https://www.youtube.com/watch?v=aDmDVOH9U-U and https://www.youtube.com/watch?v=N0XnXWM-92M are good for background, but I've linked those to you before.
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10:29 < jrayhawk> One useful principle is antioxidants do not reverse oxidative damage or even fully prevent it, they're mostly just good for limiting the recursive propagation of peroxyl radicalization.
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10:30 < jrayhawk> No pill will reverse a fire.
10:31 < jrayhawk> So you have to think in terms of appropriately limiting the kindling, appropriately limiting the fire sources, and making sure you don't run out of suppression resources.
10:33 < jrayhawk> Another principle is oxidative stress, inflammation, and micronutrient insufficiency are all mutually recursive.
10:37 < jrayhawk> Infection in general, lower respiratory infections moreso, and COVID in particular is powerful at draining glutathione, draining myeloid differentiation factors, most notably calcifediol but less significantly retinoids, driving up interleukin 6, and causing a failure of T-cell antigen training to take place.
10:49 < jrayhawk> Some of the most powerful trials we've seen in the acute setting have been of calcifediol https://pubmed.ncbi.nlm.nih.gov/32871238/ retinoid https://www.medrxiv.org/content/10.1101/2022.03.05.22271959v1 https://scholar.google.com/scholar?q=Al-Sumiadai+7347-7350 , arginine for making more room for mucous https://pmc.ncbi.nlm.nih.gov/articles/PMC8428476/
10:58 < jrayhawk> and similarly with mixed eicosapentaenoic acid and docosahexaenoic acid (essential for producing many immune molecules such as resolvins, protectins, lipoxins, maresins, etc. https://link.springer.com/article/10.1186/s12967-021-02795-5
11:03 < jrayhawk> But this is only the most obvious layer of treatment. Even in the earliest days, the Chinese government was publishing that severe and mortality of COVID-19 were correlated with other manifestations of the metabolic syndrom such as obesity, hypertension, and heart disease at relative risk ratios of 8 or 12. The reason being is that *all of those diseases* are other manifestations of recursive 
11:03 < jrayhawk> feedback cycles of inappropriate oxidative stress, inflammation, and micronutrient insufficiency.
11:10 < jrayhawk> Type 2 diabetes is superoxide-driven shutdown of GLUT4 transporters as part of mitochondrial throughput problems, be they caused by exogenous oxidative stress, inflammation, or electron transport chain cofactor deficiency. Atherosclerosis is the body trying to manage the catastrophe of oxidized apolipoprotein B100. Hypertension is from dysregulated renin/aldeosterone/angiotensin and glomarular 
11:10 < jrayhawk> filtration throughput problems. Obesity is cytokine-induced hypothalamic leptin resistance, such as IL-6 getting released by macrophages trying to clean up leaky adipocytes that are combusting from recursive lipid peroxidation.
11:11 < jrayhawk> All of them are rooted in misalignments of oxidative stress, inflammation, and micronutrient insufficiency, all of them feed back into eachother by causing further misalignments.
11:12 < hprmbridge> kanzure> now do metabolic syndrome
11:12 < jrayhawk> eh, i have done it in the past
11:13 < hprmbridge> kanzure> partial credit awarded.
11:20 < jrayhawk> Severe COVID and long COVID are already a bunch of exacerbations of pre-existing metabolic and immunological problems, but the lack of T-cell training resources and subsequent failure to transition from innate immune response to adaptive creates a lot of big long term signal-to-noise problems in the adaptive immune system resulting in a lot of wacky forms of autoimmunity.
11:21 < jrayhawk> wacky *additional* forms
11:23 < jrayhawk> People with long COVID have to be much, much more conscientious about avoiding immunogens and providing myeloid differentiation factors and resolving factors than normal people do in order to walk back the adaptive immune system's mistakes.
11:26 < jrayhawk> sorry, way back when I said "they are particularly vulnerable to effects from additionall sources of oxidative stress, such as inflammation or insufficiency of oxidative stress." that last term was supposed to be "antioxidants"
11:26 < hprmbridge> Eli> Ok interesting. I have seen some of the data on IFR for covide that came out. Covid basically didn't exist for healthy people under a certain age.
11:29 < jrayhawk> Yeah, most of this stuff takes decades of continuous fucking up to manifest as serious problems.
11:44 < jrayhawk> https://diyhpl.us/~jrayhawk/the_metabolic_syndrome/10.1056-NEJM196205172662001-a-controlled-clinical-trial-of-a-diet-high-in-unsaturated-fat-in-preventing-complications-of-atherosclerosis-figure_8.png 
11:44 < jrayhawk> https://diyhpl.us/~jrayhawk/the_metabolic_syndrome/10.1056-NEJM196205172662001-a-controlled-clinical-trial-of-a-diet-high-in-unsaturated-fat-in-preventing-complications-of-atherosclerosis-figure_14.png e.g. 8 years for adipocyte droplet turnover alone
11:45 < jrayhawk> let alone membrane turnover
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12:12 < jrayhawk> oh yeah, calcitriol, was pretty dramatic, too https://pmc.ncbi.nlm.nih.gov/articles/PMC8425676/
12:15 < hprmbridge> kanzure> we should fix warren at some point
12:25  * L29Ah chomps ground flaxseed
12:27 < jrayhawk> L29Ah: radioisotype studies indicate that human elongase and dehydrogenase are very nearly useless at converting alpha-linolenic acid to anything useful.
12:34 < L29Ah> seem useful enough to me
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13:03 < jrayhawk> mechanistic https://www.sciencedirect.com/science/article/pii/S0022227520315765 observational https://pubmed.ncbi.nlm.nih.gov/16825676/
13:13 < L29Ah> skimmed the second paper, seems inconclusive to me; also mustard oil as an example of ALA supplementation, seriously?
13:14 < L29Ah> vs fish oil
13:23 < jrayhawk> observational stuff is always inconclusive
13:25 < L29Ah> https://tinystash.undef.im/il/32N3oHNHKcVNWMEMrHgfs7jdxHtXQRTohFU43tfm2cTjN6x8EheZJB9woiRUNwexWcvqsaBSuZbh82iYvFEPbotC.png
13:25 < L29Ah> wtf seems like i don't understand something about lipid metabolism, how could it have been eliminated completely so quickly?
13:25 < jrayhawk> i also doubt the first papers 20:5n-3 to 22:6n-3 claim given how every other mechanistic experiment went on that subject
13:26 < jrayhawk> L29Ah: polyunsaturated fatty acids are preferentially burned in OxPhos because they're dangerous to keep in the body.
13:27 < jrayhawk> Most of those polyunsaturated fatty acids were destined to be removed via the lungs or urination as long as the dose is small enough to partition it that way.
13:28 < jrayhawk> Or, rather, the atomic constituents.
13:35 < jrayhawk> A major cause of metabolic and immunological disease is overloading the energy requirements of the body with polyunsaturated fatty acids and subsequently partitioning their propensity for spontaneous oxidation towards the vulnerable storage media of adipocytes and phosopholipids membranes in general.
13:36 < jrayhawk> This is hard to do with flaxseeds and fish, though.
13:37 < hprmbridge> kanzure> https://github.com/chesterzelaya/tech-tree
13:38 < jrayhawk> Typically you need to start soaking foods in dense PUFA-rich isolates like peanut oil in order to get there
13:42 < jrayhawk> Women will happily store a (very literal) assload of docosahexaenoic acid and eicosapentaenoic acid for future use in encephalizing babies, though.
13:49 < jrayhawk> I, for one, am compelled by evolutionary forces beyond my control to appreciate their sacrifice.
13:51 < L29Ah> https://ichef.bbci.co.uk/news/976/cpsprodpb/5CDF/production/_87157732_thinkstockphotos-506934235.jpg
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17:16 < hprmbridge> .monokhrome> Are there any experimental treatments that reverse atherosclerotic plaques once they've built up?
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17:24 < jrayhawk> this is such a weird category error of a question i don't even know how to answer it
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17:26 < jrayhawk> plaques happen when the rate of fatty acid and/or calcium entrapment exceeds macrophage cleanup capacity
17:26 < jrayhawk> is "having functioning macrophages" a "treatment"? do you conceptualize a treatment that would replace the physiological function of macrophages?
17:30 < hprmbridge> .monokhrome> So what, it's a matter of upgrading the ageing immune system?
17:31 < jrayhawk> age is cope causality
17:33 < L29Ah> jrayhawk: no it is not a treatment as there is no evidence that plaques ever become smaller afaik
17:33 < jrayhawk> that happens all the time in the literature
17:34 < jrayhawk> you solve the problem by lowering the amount of oxidized apolipoprotein B100, lowering expression of adhesion, lowering expression of permeability, lowering cellular oxidative fragility, improving myeloid differentiation, and freeing up immune capacity
17:34 < hprmbridge> .monokhrome> Yeah, that was my impression, they don't regress
17:35 < jrayhawk> https://scholar.google.com/scholar?q=atherosclerosis+regression
17:35 < jrayhawk> please stop listening to dumbshit doctors and start reading papers
17:39 < jrayhawk> standard of care is a poltiical epistemology that is perpetually 60 years out of date unless some drug company dumps hundreds of millions of dollars into buying every doctor in the U.S. dinner over which they pitch n-recursive-depth shared knowledge of a working treatment
17:40 < jrayhawk> er, political
17:40 < hprmbridge> kanzure> grandma emails to ask "why not get more AI expertise and get one of those offers from Mark Zuckerberg?"
17:51  * L29Ah still didn't do his frozen-sprat-blendering DHA extraction experiment :[
17:51 < jrayhawk> nobody is going to spend $100m to pitch "not eating opioid-agonizing chemokine-receptor-agonizing agricultural waste" to doctors, so we're stuck with the American Heart Association, which rose to prominance on grants from Proctor & Gamble for the express purpose of promoting partially hydrogenated rapeseed oil, being paid to promote the lipid hypothesis 40 years after randmized controlled trials 
17:51 < jrayhawk> invalidated it and, statins 20 years after NMR spectroscopy invalidated those.
17:54 < jrayhawk> Who wants to lose their liability insurance and medical license by offering to make good on the sentiment "atherosclerosis is easy to treat, we just haven't solved the coordination problem needed to allow ourselves to do it?"
17:56 < jrayhawk> It is difficult to get a man to understand something when getting out from under $300k of medical school debt depends on his not understanding it.
18:05 < L29Ah> MuaddibLLM: how could one solve this problem?
18:05 < MuaddibLLM> Decentralized health communities sharing outcomes data, direct-to-consumer biomarker testing, and maybe medical tourism to jurisdictions with more experimental freedom - basically route around the gatekeepers until the evidence becomes undeniable.
18:15 < jrayhawk> monokhrome: http://youtube.com/watch?v=8uQuF9isqFo is good background and acts as a public communications version of https://pubmed.ncbi.nlm.nih.gov/15383655/ , https://vimeo.com/152402052 builds a bunch of good intuitions about chemokine receptors upregulating surface expression of adhesive proteoglycans and releasing of tight barrier junctions allowing endothelial transmigration (e.g. CXCR3 
18:15 < jrayhawk> knockout mice don't get atherosclerosis https://scholar.google.com/scholar?q=cxcr3+knockout+atherosclerosis ), https://pubmed.ncbi.nlm.nih.gov/21248165/ is one of the most important papers you'll ever read, discussing grain prolamines as cause of CXCR3-induced claudin and occludin permeability, https://pubmed.ncbi.nlm.nih.gov/34223877/ and https://www.mdpi.com/2227-9717/7/8/513 as other sources of 
18:15 < jrayhawk> major membrane and immune disruption, https://sci-hub.ru/downloads/2019-01-22//16/10.1007@s10989-019-09813-7.pdf the random binding affinities of which also commonly include opioid receptors, https://www.westonaprice.org/health-topics/abcs-of-nutrition/beyond-good-and-evil/#:~:text=a%20balance%20between is a very concise summary of calcium management, 
18:15 < jrayhawk> https://diyhpl.us/~jrayhawk/the_metabolic_syndrome/mesa-alignment-diet-trials.txt are various dietary trials solving the metabolic syndrome and autoimmunity generally.
18:21 < L29Ah> where is muurkha?
18:22 < L29Ah> was he consumed by entropy or just by our discordian overlords?
18:23 < L29Ah> i need a sitrep from Argentina that seems to exert increasing pull on me
18:31 < hprmbridge> kanzure> "They went to a Las Vegas conference this month that promised pathways to an “unlimited lifespan.” But at least two attendees left in ambulances and were hospitalized in critical condition, requiring ventilators to breathe. The two women, who are recovering, fell ill after receiving peptide injections at a conference booth."
18:31 < jrayhawk> What were the peptide(s)?
18:31 < hprmbridge> kanzure> eh, weird to blame the peptides. that conference is kinda wacky. a lot of woo going on there.
18:31 < jrayhawk> or is that a trade secret
18:32 < hprmbridge> kanzure> I think this is just premature correlation finger p9inting most likely?
18:32 < hprmbridge> kanzure> https://www.propublica.org/article/peptide-injections-raadfest-rfk-jr
18:34 < jrayhawk> https://drkentholtorf.com/medical-literature/peptides:-unlock-the-secret-to-longevity
18:36 < jrayhawk> sounds like he'd be the type to employ a wide variety of them all at once
18:36 < hprmbridge> .monokhrome> If they can affect your metabolism strongly enough to cure disease, I'm sure they can affect it strongly enough for there to be safety issues
18:38 < jrayhawk> yeah, ironically the people he'd most want to treat are going to be the people with the angriest immune systems looking for an excuse to do something violent
18:39 < jrayhawk> monokhrome: if you chew through all that stuff and want more, let me know
19:16 < fenn> L29Ah: you can /msg xentrac
19:39 < hprmbridge> Eli> Grandmas right!
21:30 < hprmbridge> kanzure> it's a misunderstanding of who those 1 billion dollar offers are going to.
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--- Log closed Sun Aug 03 00:00:59 2025